EP4083042A1 - Spiro ring-containing quinazoline compound - Google Patents
Spiro ring-containing quinazoline compound Download PDFInfo
- Publication number
- EP4083042A1 EP4083042A1 EP20905322.2A EP20905322A EP4083042A1 EP 4083042 A1 EP4083042 A1 EP 4083042A1 EP 20905322 A EP20905322 A EP 20905322A EP 4083042 A1 EP4083042 A1 EP 4083042A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- compound
- alkoxy
- cycloalkyl
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 125000003003 spiro group Chemical group 0.000 title claims abstract description 10
- -1 quinazoline compound Chemical class 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 188
- 239000003814 drug Substances 0.000 claims abstract description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- 125000001188 haloalkyl group Chemical group 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 15
- 150000004677 hydrates Chemical class 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 2
- 229910003827 NRaRb Inorganic materials 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 101710113436 GTPase KRas Proteins 0.000 abstract description 17
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 102200006538 rs121913530 Human genes 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 27
- 102000016914 ras Proteins Human genes 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 25
- 108010014186 ras Proteins Proteins 0.000 description 25
- 230000035772 mutation Effects 0.000 description 21
- 206010028980 Neoplasm Diseases 0.000 description 20
- 238000000034 method Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 102200124918 rs121913250 Human genes 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 230000014759 maintenance of location Effects 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- 101100193693 Kirsten murine sarcoma virus K-RAS gene Proteins 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- 230000001028 anti-proliverative effect Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- PEMUGDMSUDYLHU-ZEQRLZLVSA-N 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile Chemical compound ClC=1C=CC=C2C=CC=C(C=12)N1CC=2N=C(N=C(C=2CC1)N1C[C@@H](N(CC1)C(C(=C)F)=O)CC#N)OC[C@H]1N(CCC1)C PEMUGDMSUDYLHU-ZEQRLZLVSA-N 0.000 description 3
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 3
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-UHFFFAOYSA-N 0.000 description 3
- GSDQYSSLIKJJOG-UHFFFAOYSA-N 4-chloro-2-(3-chloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1NC1=CC=CC(Cl)=C1 GSDQYSSLIKJJOG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 3
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 3
- 229940124988 adagrasib Drugs 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical compound FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical group ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical group NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 2
- 102100039788 GTPase NRas Human genes 0.000 description 2
- 102000018898 GTPase-Activating Proteins Human genes 0.000 description 2
- 108091006094 GTPase-accelerating proteins Proteins 0.000 description 2
- 108091006109 GTPases Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 2
- 101000628562 Homo sapiens Serine/threonine-protein kinase STK11 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 description 2
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 2
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- MSGMXYUAWZYTFC-UHFFFAOYSA-N sodium;2,2,2-trifluoroethanolate Chemical compound [Na+].[O-]CC(F)(F)F MSGMXYUAWZYTFC-UHFFFAOYSA-N 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- HRURFOBSNYPWDM-UHFFFAOYSA-N (5-methyl-1h-indazol-4-yl)boronic acid Chemical compound CC1=CC=C2NN=CC2=C1B(O)O HRURFOBSNYPWDM-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical compound O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 description 1
- AIWUZVDERRAYFV-UHFFFAOYSA-N 1-(2-methoxyethyl)piperidin-4-ol Chemical compound COCCN1CCC(O)CC1 AIWUZVDERRAYFV-UHFFFAOYSA-N 0.000 description 1
- VVZIOWHNGJEMGE-UHFFFAOYSA-N 1-[7-[6-cyclopropyl-8-ethoxy-2-[1-(2-methoxyethyl)piperidin-4-yl]oxy-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]-2-fluoroprop-2-en-1-one Chemical compound CCOC1=C2C(=CC(=C1C3=C(C=CC4=C3C=NN4)C)C5CC5)C(=NC(=N2)OC6CCN(CC6)CCOC)N7CCC8(CC7)CN(C8)C(=O)C(=C)F VVZIOWHNGJEMGE-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- HTFNVAVTYILUCF-UHFFFAOYSA-N 2-[2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]anilino]-5-methyl-11-methylsulfonylpyrimido[4,5-b][1,4]benzodiazepin-6-one Chemical compound CCOc1cc(ccc1Nc1ncc2N(C)C(=O)c3ccccc3N(c2n1)S(C)(=O)=O)C(=O)N1CCC(CC1)N1CCN(C)CC1 HTFNVAVTYILUCF-UHFFFAOYSA-N 0.000 description 1
- QPEJAHMNOVMSOZ-UHFFFAOYSA-N 2-azaspiro[3.3]heptane Chemical compound C1CCC21CNC2 QPEJAHMNOVMSOZ-UHFFFAOYSA-N 0.000 description 1
- TYCFGHUTYSLISP-UHFFFAOYSA-N 2-fluoroprop-2-enoic acid Chemical compound OC(=O)C(F)=C TYCFGHUTYSLISP-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241001125671 Eretmochelys imbricata Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 description 1
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010064912 Malignant transformation Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 1
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- 102000001694 Signal Transducing Adaptor Proteins Human genes 0.000 description 1
- 108010029228 Signal Transducing Adaptor Proteins Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 125000005619 boric acid group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229940125808 covalent inhibitor Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 230000036212 malign transformation Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000018883 protein targeting Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000011802 pulverized particle Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 102200124919 rs121913237 Human genes 0.000 description 1
- 102220011004 rs121913237 Human genes 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention belongs to the field of medicinal chemistry, and particularly to a spiro ring-containing quinazoline compound, a preparation method therefor, and use of the compound as a K-Ras G12C inhibitor in preparing antitumor medicaments.
- Ras protein family members are important signal transduction molecules in cells, and play an important role in the growth and development. Extensive analysis and study of in vitro tumor cells, animal models and human tumor samples indicate that the over-activation of Ras family proteins is an early event in the development of human tumors and is one of the important causes of the development and progression of many types of cancer. Targeting Ras proteins and inhibiting the Ras protein activity are therefore important means of treating related tumors.
- Ras protein exists in two forms. It is in an unactivated resting state when bound to GDP, and when a cell receives signals such as growth factor stimulation, it is bound to GTP and thus activated. Activated Ras proteins recruit a variety of signal-transducing adaptor proteins to promote phosphorylation of downstream signaling molecules such as ERK and S6, thereby activating the Ras signal transduction pathway and regulating the growth, survival, migration and differentiation of cells. Ras proteins can hydrolyze GTP back to GDP due to their GTPase activity. Besides, the GTPase-activating proteins (GAPs) in cells interact with Ras, greatly improving the GTPase activity of Ras and thereby preventing Ras proteins from being overly activated.
- GAPs GTPase-activating proteins
- Mutations in the K-Ras, H-Ras and N-Ras proteins of the Ras protein family are one of the common genetic mutations in a variety of tumors, and are a major factor leading to over-activation of Ras proteins in tumors.
- Ras proteins with these mutations have unregulated activity; they are stably bound to GTP and constantly activated, thereby promoting the growth, migration and differentiation of tumor cells.
- those in K-Ras proteins are the most common ones, accounting for 85% of all Ras mutations, while those in N-Ras (12%) and H-Ras (3%) are relatively rare.
- K-Ras mutations are very common in many types of cancer, including pancreatic cancer (95%), colorectal cancer (45%), lung cancer (25%), etc., while relatively rare ( ⁇ 2%) in breast cancer, ovarian cancer and brain cancer.
- K-Ras mutations mainly occur at position G12, and G12C mutation is the most common one.
- NSCLC non-small cell lung cancer
- K-Ras G12C K-Ras G12C
- G12V and G12D are the second most common mutations.
- K-Ras mutations in non-small cell lung cancer generally do not coexist with EGFR, ALK, ROS1, RET and BRAF mutations, but coexist with STK11, KEAP1, TP53 and other mutations, suggesting that K-Ras mutations may be involved in malignant transformation, proliferation and invasion of cells synergistically with STK11, KEAP1, TP53 and other mutations.
- abnormal activation of Ras proteins is also involved in non-tumor diseases including diabetes, neurodegenerative diseases, etc.
- Ras protein-targeting small-molecule compounds can benefit a large number of cancer patients with specific genetic mutations and non-cancer patients with over-activation of the Ras pathway.
- K-Ras G12C muteins as a leading therapeutic target, have not been extensively researched at present, and only a few compounds, such as AMG510 of Amgen and MRTX849 of Mirati, have been under clinical research.
- a K-Ras G12C mutation-targeting covalent inhibitor ARS-1620 was reported in Cell ( Cell, 2018, 172: 578-589 ).
- the present invention aims to provide a compound of a structural general formula as shown in formula (1), isomers thereof, crystalline forms thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof: wherein in formula (1):
- R 1 is H, F, Cl, Me, Et, vinyl, isopropyl, ethynyl or cyclopropyl.
- R 2 is CH 3 CH 2 O-, CF 3 CH 2 O-, CHF 2 CH 2 O-,
- R 3 is
- R 4 is H, F, CN, Me, CF 3 ,
- R 5 is:
- R 3 when R 3 is and R 4 is F, CN, Me, CF 3 , or when R 3 is
- R 5 is:
- a representative compound of general formula (1) of the present invention has one of the following structures:
- Another aspect of the present invention aims to provide a compound with a structural general formula as shown in formula (2), isomers thereof, crystalline forms thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof: wherein in formula (2):
- R 3a is
- R 5a is: H, or
- a representative compound of general formula (2) of the present invention has one of the following structures:
- Another aspect of the present invention aims to provide a compound with a structure as shown in general formula (3), isomers thereof, crystalline forms thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof:
- R 5b is: H
- Another purpose of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the compounds of general formulas (1) through (3), the isomers thereof, the crystalline forms thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof of the present invention as active ingredients.
- Still another purpose of the present invention is to provide use of the compounds, the isomers thereof, the crystalline forms thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof of the present invention described above in preparing a medicament for treating RAS-associated diseases.
- the inventors found that in the compounds of general formulas (1) through (3), when R 5 (or R 5a or R 5b ) is a spiro ring or other substituted heterocyclic ring, the compounds have very high K-RAS G12C inhibitory activity, meanwhile, the pharmacokinetic properties of the compounds are greatly improved, and the in vivo activity of the compounds is enhanced.
- the inventors found that when position 2 (substituent R 4 ) of acrylamide is substituted with a F atom that is small in size, the compounds also have good K-RAS G12C inhibitory activity and pharmacokinetic properties.
- the compounds of general formulas (1) through (3) described above may be synthesized using standard synthetic techniques or well-known techniques in combination with the methods described herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of the compounds may be obtained synthetically or commercially. The compounds described herein and other related compounds having different substituents may be synthesized using well-known techniques and starting materials, including the methods found in March, ADVANCED ORGANIC CHEMISTRY, 4th Ed., (Wiley 1992 ); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4th Ed., Vols.
- the compounds described herein are prepared according to methods well known in the art. However, the conditions involved in the methods, such as reactants, solvent, base, amount of the compound used, reaction temperature and time required for the reaction are not limited to the following explanation.
- the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art to which the present invention pertains.
- the present invention also provides a method for preparing the compounds of general formulas (1) through (3), which are prepared using general reaction scheme 1 below:
- the preparation may be performed according to general reaction scheme 1, wherein T represents H, F, Cl or I, T 1 represents R 5 , R 5a or R 5b , T 2 represents R 3 or R 3a , T 3 represents R 1 or R 1a , T 4 represents R 2 or R 2a , and T 5 represents R 4 or R 4a ; R 1 , R 1a , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a and R 5b are defined as above, PG represents a protecting group, and X represents boric acid, a borate or a trifluoroborate.
- “Pharmaceutically acceptable” herein refers to a substance, such as a carrier or diluent, which will not cause a compound to lose its biological activity or properties. It is relatively non-toxic; for example, when an individual is given a substance, it will not cause unwanted biological effects or interact with any component contained therein in a deleterious manner.
- pharmaceutically acceptable salt refers to a form of a compound that does not cause significant irritation to the organism for drug administration or eliminate the biological activity and properties of the compound.
- pharmaceutically acceptable salts are obtained by reacting the compounds of general formulas (1) through (3) with acids, e.g.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid and nitric acid
- organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid and p -toluenesulfonic acid
- acidic amino acids such as aspartic acid and glutamic acid.
- references to pharmaceutically acceptable salts include solvent addition forms or crystal forms, especially solvates or polymorphs.
- a solvate contains either stoichiometric or non-stoichiometric amount of solvent and is selectively formed during crystallization with pharmaceutically acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
- the solvates of the compounds of general formulas (1) through (3) are conveniently prepared or formed according to the methods described herein.
- the hydrates of the compounds of general formulas (1) through (3) are conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, wherein the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
- the compounds mentioned herein can exist in both non-solvated and solvated forms. In general, the solvated forms are considered equivalent to the non-solvated forms for purposes of the compounds and methods provided herein.
- the compounds of general formulas (1) through (3) are prepared into different forms, including but not limited to amorphous, pulverized and nanoparticle forms.
- the compound of general formula (1) includes crystalline forms, and may also be polymorphs. Polymorphs include different lattice arrangements of the same elements of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystalline forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may lead to monocrystalline form being dominant.
- the compounds of general formulas (1) through (3) have axial chiralities and/or chiral centers and thus occur in the form of a racemate, racemic mixture, single enantiomer, diastereomeric compound and single diastereomer.
- Each of these axial chiralities will independently produce two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention.
- the present invention is meant to include all such isomeric forms of these compounds.
- alkyl refers to a saturated aliphatic hydrocarbon group, including linear and branched groups containing 1 to 6 carbon atoms. Lower alkyl containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n -butyl, isobutyl or tert-butyl, is preferred.
- alkyl includes unsubstituted and substituted alkyl, particularly alkyl substituted with one or more halogens. Preferred alkyl is selected from CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CF 3 CH, i Pr, n Pr, i Bu, n Bu and t Bu.
- alkenyl refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon double bonds, including linear and branched groups containing 1 to 6 carbon atoms. Lower alkenyl containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, is preferred.
- alkynyl refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon triple bonds, including linear and branched groups containing 1 to 6 carbon atoms. Lower alkenyl containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, is preferred.
- cycloalkyl refers to a 3- to 6-membered all-carbon monocyclic aliphatic hydrocarbon group, wherein one or more of the rings may contain one or more double bonds, but none of them has a fully conjugated ⁇ -electron system.
- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, and cyclohexadiene are examples of compounds that are commonly known as cyclobutyl.
- alkoxy refers to an alkyl group that bonds to the rest of the molecule through an ether oxygen atom.
- Representative alkoxy groups are ones having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec -butoxy and tert -butoxy.
- alkoxy includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens.
- Preferred alkoxy is selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO and t- BuO.
- heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S or N) and it is monocyclic or polycyclic; for example, a monocyclic heteroaryl ring fuses with one or more carbocyclic aromatic groups or other monocyclic heterocyclyl groups.
- heteroaryl examples include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, and pyrrolopyrimidinyl.
- heterocycloalkyl refers to a saturated or partially unsaturated ring system group containing one or more heteroatoms (O, S or N), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized as a ring atom.
- heterocycloalkyl ring system may be a monocyclic, bicyclic, spiro or polycyclic ring system.
- Heterocycloalkyl may link to the rest of the molecule through one or more ring carbons or heteroatoms.
- heterocycloalkyl examples include, but are not limited to, pyrrolidine, piperidine, N -methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1 H ,3 H ) -dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-azaspiro[3.3]heptane, etc.
- halogen refers to fluorine, chlorine, bromine, or iodine.
- halo or halogenated
- the term “halo” (or “halogenated”) before a group name indicates that the group is partially or fully halogenated, that is, substituted in any combination by F, Cl, Br or I, preferably by F or Cl.
- acceptable means that a formula component or an active ingredient does not unduly adversely affect a general therapeutic target's health.
- treatment include alleviating, inhibiting, or ameliorating a symptom or condition of a disease; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of the disease or symptom, e.g., controlling the progression of the disease or condition; alleviating the disease or symptom; causing the disease or symptom to subside; alleviating a complication caused by the disease or symptom, or preventing or treating a sign caused by the disease or symptom.
- a compound or pharmaceutical composition when administered, can ameliorate a disease, symptom, or condition, particularly meaning ameliorating the severity, delaying the onset, slowing the progression, or reducing the duration of the disease. Fixed or temporary administration, or continuous or intermittent administration, may be attributed to or associated with the administration.
- the “active ingredient” refers to compounds of general formulas (1) through (3), and pharmaceutically acceptable inorganic or organic salts of the compounds of general formulas (1) through (3).
- the compounds of the present invention may contain one or more asymmetric centers (axial chirality) and thus occur in the form of a racemate, racemic mixture, single enantiomer, diastereomeric compound and single diastereomer.
- Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each of these asymmetric centers will independently produce two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention.
- the present invention is meant to include all such isomeric forms of these compounds.
- composition refers to a compound or composition that, when administered to an individual (human or animal), is capable of inducing a desired pharmacological and/or physiological response by local and/or systemic action.
- administering refers herein to the direct administration of the compound or composition, or the administration of a prodrug, derivative, analog or the like of the active compound.
- the present invention provides a method for using the compound or pharmaceutical composition of the present invention to treat diseases, including but not limited to conditions involving G12C K-Ras, G12C H-Ras and/or G12C N-Ras mutations (e.g., cancer).
- diseases including but not limited to conditions involving G12C K-Ras, G12C H-Ras and/or G12C N-Ras mutations (e.g., cancer).
- a method for treating cancer comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition of any of the aforementioned compounds of structural general formulas (1) through (3) protected.
- the cancer is mediated by K-Ras, H-Ras and/or G12C N-Ras mutations.
- the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-associated polyposis, or colorectal cancer.
- the compound and the pharmaceutically acceptable salt thereof of the present invention can be prepared into various preparations which include the compound or the pharmaceutically acceptable salt thereof disclosed herein in a safe and effective amount range and a pharmaceutically acceptable excipient or carrier, wherein the "safe and effective amount” means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the safe and effective amount of the compound is determined according to the age, condition, course of treatment and other specific conditions of a treated subject.
- pharmaceutically acceptable excipient or carrier refers to one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
- Cosmetic means that the components of the composition are capable of intermixing with the compound of the present invention and with each other, without significantly diminishing the pharmaceutical efficacy of the compound.
- Examples of pharmaceutically acceptable excipients or carriers are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oil (e.g., soybean oil, sesame oil, peanut oil or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol or sorbitol), emulsifiers (e.g., Tween ® ), wetting agents (e.g., sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- cellulose and its derivatives e.g., sodium carboxymethylcellulose, sodium ethylcellulose or cellulose acetate
- gelatin talc
- solid lubricants e.g
- the compound of the present invention When the compound of the present invention is administered, it may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously) or topically.
- Solid dosage forms for oral administration include capsules, tablets, pills, pulvises and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol, such
- Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may include opacifying agents, and the active compound or compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and wax-based substances. If necessary, the active compound can also be in microcapsule form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage form may include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances.
- inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide
- the composition may also include adjuvants, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents.
- adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents.
- Suspensions in addition to the active compound, may include suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate and agar, or mixtures of these substances.
- compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for redissolving into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- Dosage forms for topical administration of the compound of the present invention include ointments, pulvises, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants that may be required if necessary.
- the compound of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) to be treated, wherein the administration dose is a pharmaceutically effective administration dose.
- a mammal such as a human
- the daily dose of administration is usually 1-2000 mg, preferably 50-1000 mg.
- factors as the route of administration, the health condition of the patient and the like will also be considered, which are well known to skilled physicians.
- the present invention uses the following abbreviations: CD 3 OD for deuterated methanol; MeCN for acetonitrile; DCM for dichloromethane; DIPEA for diisopropylethylamine; dioxane for 1,4-dioxane; DMF for dimethylformamide; K 3 PO 4 for potassium phosphate; min for minute; MS for mass spectroscopy; NaH for sodium hydride; NMR for nuclear magnetic resonance; Pd 2 (dba) 3 for tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl 2 for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; TFA (CF 3 COOH) for trifluoroacetic acid; TLC for thin layer chromatography; THF for tetrahydrofuran; and Xantphos for 4,5-bis(diphenylphosphane)-9,9-dimethylxanthen
- FIG. 1 shows the inhibition of the phosphorylated ERK (pERK) level in cells by compounds.
- Example 1 Synthesis of 1-(7-(6-Cyclopropyl-8-ethoxy-2-((1-(2-methoxyethyl)piperidin-4-yl)oxy)-7-(5-methyl-1 H -indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-fluoroprop-2-en-1-one (Compound 1)
- Trifluoroethanol (0.9 g, 8.4 mmol) was dissolved in anhydrous DMF (10 mL). NaH was added under ice bath. The mixture was stirred at room temperature for 5 min to obtain sodium trifluoroethoxide.
- Compound 1-4 (4.1 g, 5.6 mmol) was dissolved in anhydrous THF (40 mL). The solution of sodium trifluoroethoxide in DMF prepared above was added. The mixture was stirred at room temperature overnight. After the reaction was completed, water was added, followed by EA for extraction. The organic phase was dried and concentrated, and the residue was subjected to column chromatography to obtain compound 1-5 (4.5 g, 99% yield).
- the target compound 2-341 was obtained using different starting materials according to a synthesis method similar to that in Example 1.
- Table 1 Compound Compound structure [M+H] + Compound Compound structure [M+H] + 2 698.4 3 734.4 4 684.4 5 738.3 6 792.4 7 747.4 8 691.4 9 727.4 10 694.3 11 712.3 12 728.3 13 708.3 14 722.4 15 736.4 16 718.3 17 748.4 18 759.3 19 802.3 20 812.4 21 812.4 22 800.4 23 801.4 24 799.4 25 801.4 26 706.3 27 734.4 28 767.4 29 786.3 30 770.4 31 766.4 32 752.3 33 756.3 34 756.3 35 734.4 36 756.3 37 738.3 38 756.3 39 735.4 40 753.3 41 761.3 42 779.3 43 762.3 44 780.3 45 714.3 46 732.3 47 713.4 48 731.3 49 781.3 50 799.2 51 698.3 52 71
- the compounds of the present application may have axial chirality. Compounds with axial chirality can be resolved to obtain two chiral isomers.
- a first chiral isomer 174-a; retention time on the chromatography column: 8.994 min; and a second chiral isomer: 174-b; retention time on the chromatography column: 14.583 min.
- 270 Same as those for compound 142 except that the mobile phase is ethanol- n -hexane (30/70) a first chiral isomer: 270-a; retention time on the chromatography column: 7.280 min; and a second chiral isomer: 270-b; retention time on the chromatography column: 12.962 min.
- H358 cells were seeded in a 24-well plate. After one day of growth, a test compound (at a concentration of 1 ⁇ M) was added. After 24 h of action of the compound, the cells were lysed, and the cell lysate was transferred to a 96-well ELISA plate. The levels of pERK and ERK in the lysate were measured using an ELISA kit (abcam 176660). The ratio of pERK to ERK was calculated and compared with that of the DMSO group, and the percentage of inhibition of pERK activity by the compound was calculated. The results are shown in Table 3 below. Table 3.
- Antiproliferative activity of the compounds of the present invention against H358 cells Compound IC 50 Compound IC 50 Compound IC 50 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 ++ 8 ++ 9 +++ 10 ++ 11 +++ 12 +++ 13 ++ 14 ++ 15 +++ 16 ++ 17 +++ 18 ++ 19 ++ 20 +++ 21 +++ 22 ++ 23 +++ 24 ++ 25 +++ 26 ++ 27 ++ 28 ++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 ++ 38 ++ 39 +++ 40 +++ 41 +++ 42 ++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 ++ 49 +++ 50 +++ 51 +++ 52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 +++ 59 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64 ++ 65 +++ 66 67 ++ 68 ++ 69 +++ 70 ++ 71
- the antiproliferative activity of most of the compounds of the present invention against H358 cells is less than 0.3 ⁇ M, and when R 5 (or R 5a or R 5b ) is a spiro ring or other substituted heterocyclic ring, the compounds have very high K-RAS G12C inhibitory activity.
- Compounds 131, 142 and 171 all have good antiproliferative activity against H358 cells, with their IC 50 values being 1.5 nM, 2.5 nM and 1.4 nM, respectively, while the IC 50 values of the reference compounds B and C were 4.6 nM and 5.1 nM, respectively, indicating that the cell activity of the compounds was greatly improved after cyclization of the amino groups on the side chains of the compounds.
- the compounds when position 2 (substituent R 4 ) of acrylamide is substituted with a F atom that is small in size, the compounds also have very high K-RAS G12C inhibitory activity.
- the compounds were administered by intravenous injection at a dose of 2 mg/kg and oral gavage at a dose of 10 mg/kg (0.5% CMC-Na suspension).
- 15 male ICR mice were selected for each group, and each mouse was subjected to blood collection at 3 discrete time points, with 3 mice per time point.
- the time points of sampling were as follows: before the administration, and at 5 min, 15 min, 30 min, 1 h, 3 h, 5 h, 8 h, 12 h and 24 h after the administration. 80 ⁇ L of blood was collected from the eye sockets or the hearts of the mice at each of the time points after the administration.
- compound 131 has good oral absorption properties, and has improved metabolic parameters such as half-life (t 1 ⁇ 2 ), maximum plasma concentration (C max ), area under the drug-time curve (AUC 0-t ), and oral bioavailability.
- compound 171 has better metabolic parameters
- compound 142 also has significantly improved metabolic parameters such as C max and AUC 0-t , indicating that the metabolic properties of the compound are well improved after the amino groups on the side chain are cyclized.
- the metabolic properties of the compounds similar to compounds 131 and 171 in the present application are also significantly improved. Good oral absorption properties are of great significance in improving the efficacy of drugs, reducing the dose of administration and reducing the costs.
- Mia PaCa-2 cells were cultured conventionally in 1640 medium containing 10% fetal bovine serum in a 37 °C/5% CO 2 incubator. After passage, the cells were collected when they reached the desired amount. 1 ⁇ 10 7 Mia PaCa-2 cells were injected into the left dorsal side of each nude mouse, and the animals were randomly grouped for administration after tumors grew to 150 mm3.
- the groups are as follows: 1) a solvent control group of 8 mice; and 2) compound 1 group, compound 2 group, compound 5 group, compound 31 group, compound 131 group, compound 142 group, compound 171 group, compound B group and compound C group, with 8 mice per group.
- mice in the solvent control group were subjected to intragastric administration of 0.5% CMC-Na once daily; mice in compound 1 group, compound 2 group, compound 5 group, compound 31 group, compound 131 group, compound 142 group, compound 171 group, compound B group and compound C group were subjected to intragastric administration of a suspension of a compound in 0.5% CMC-Na once daily.
- mice in compound 1 group, compound 2 group, compound 5 group, compound 31 group, compound 131 group, compound 142 group, compound 171 group, compound B group and compound C group were subjected to intragastric administration of a suspension of a compound in 0.5% CMC-Na once daily.
- tumor volumes and body weight of the mice were measured, and the nude mice were sacrificed on day 21 of administration.
- Table 6 Table 6.
- the compounds of the present invention have high in vivo antitumor activity; a tumor can regress after 21 consecutive days of administration at 10 mg/kg/day; compounds 1, 5, 31, 131, 142 and 171 have higher in vivo activity than reference compound B and compound C, and compounds 142 and 171 have significantly higher in vivo activity than compound C, indicating the in vivo activity of the compound is also greatly improved after the amino groups on the side chain of the compound are cyclized.
- H358 cells were plated on to a 24-well plate at 2 ⁇ 10 5 cells/well. Serially diluted compounds including AMG510, MRTX849, compound 142 and compound 171 were added. After overnight incubation, cells were lysed, and proteins were quantified and subjected to gel electrophoresis.
- FIG. 1 The results of the phosphorylated ERK (pERK) level assay by western blot are shown in FIG. 1 .
- the compounds 142 and 171 of the present invention shows stronger inhibition of the phosphorylated ERK (pERK) level in cells than the reference drugs AMG510 and MRTX849 when at the same concentration.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
- The present application claims priority to Chinese Patent application No.
CN201911386239.6 filed on Dec. 27, 2019 CN202010486384.8 filed on Jun. 1, 2020 - The present invention belongs to the field of medicinal chemistry, and particularly to a spiro ring-containing quinazoline compound, a preparation method therefor, and use of the compound as a K-Ras G12C inhibitor in preparing antitumor medicaments.
- Ras protein family members are important signal transduction molecules in cells, and play an important role in the growth and development. Extensive analysis and study of in vitro tumor cells, animal models and human tumor samples indicate that the over-activation of Ras family proteins is an early event in the development of human tumors and is one of the important causes of the development and progression of many types of cancer. Targeting Ras proteins and inhibiting the Ras protein activity are therefore important means of treating related tumors.
- An Ras protein exists in two forms. It is in an unactivated resting state when bound to GDP, and when a cell receives signals such as growth factor stimulation, it is bound to GTP and thus activated. Activated Ras proteins recruit a variety of signal-transducing adaptor proteins to promote phosphorylation of downstream signaling molecules such as ERK and S6, thereby activating the Ras signal transduction pathway and regulating the growth, survival, migration and differentiation of cells. Ras proteins can hydrolyze GTP back to GDP due to their GTPase activity. Besides, the GTPase-activating proteins (GAPs) in cells interact with Ras, greatly improving the GTPase activity of Ras and thereby preventing Ras proteins from being overly activated.
- Mutations in the K-Ras, H-Ras and N-Ras proteins of the Ras protein family are one of the common genetic mutations in a variety of tumors, and are a major factor leading to over-activation of Ras proteins in tumors. Compared to the wild-type Ras proteins, Ras proteins with these mutations have unregulated activity; they are stably bound to GTP and constantly activated, thereby promoting the growth, migration and differentiation of tumor cells. Among these mutations, those in K-Ras proteins are the most common ones, accounting for 85% of all Ras mutations, while those in N-Ras (12%) and H-Ras (3%) are relatively rare. K-Ras mutations are very common in many types of cancer, including pancreatic cancer (95%), colorectal cancer (45%), lung cancer (25%), etc., while relatively rare (< 2%) in breast cancer, ovarian cancer and brain cancer. K-Ras mutations mainly occur at position G12, and G12C mutation is the most common one. For example, in non-small cell lung cancer (NSCLC), about 50% of K-Ras mutations are K-Ras G12C, and G12V and G12D are the second most common mutations. Genomic studies show that K-Ras mutations in non-small cell lung cancer generally do not coexist with EGFR, ALK, ROS1, RET and BRAF mutations, but coexist with STK11, KEAP1, TP53 and other mutations, suggesting that K-Ras mutations may be involved in malignant transformation, proliferation and invasion of cells synergistically with STK11, KEAP1, TP53 and other mutations. In addition to tumors, abnormal activation of Ras proteins is also involved in non-tumor diseases including diabetes, neurodegenerative diseases, etc. Hence, Ras protein-targeting small-molecule compounds can benefit a large number of cancer patients with specific genetic mutations and non-cancer patients with over-activation of the Ras pathway.
- Since the discovery of Ras mutations in tumors that happened forty years ago, although we have gained deeper insight into the pathogenesis involving the Ras pathway, no clinically effective therapeutic approach targeting Ras proteins has yet come onto the market for a large number of patients with Ras protein mutations and over-activation of the Ras pathway. Therefore, the development of a high-activity small-molecule inhibitor targeted at Ras proteins, particularly the K-Ras G12C protein with high frequency of mutation, is of great clinical significance.
- K-Ras G12C muteins, as a leading therapeutic target, have not been extensively researched at present, and only a few compounds, such as AMG510 of Amgen and MRTX849 of Mirati, have been under clinical research. In 2018, a K-Ras G12C mutation-targeting covalent inhibitor ARS-1620 was reported in Cell (Cell, 2018, 172: 578-589). A class of spiro compounds with K-Ras G12C activity and anti-tumor activity in mice are reported in patent
WO2018/143315 , and a general formula A, a representative compound B (Example 35 in the patent) and a representative compound C (Example 65 in the patent) thereof are shown as the structures below (refer to the patent for the definitions of the symbols in the formula): - Currently, there is an urgent need to study and discover compounds with good K-Ras G12C activity and superior pharmacokinetic properties.
-
- R1 is H, halogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl;
- R2 is C1-C3 alkoxy, C1-C3 haloalkoxy or -NRaRb, wherein Ra and Rb are independently H, C1-C3 alkyl or C1-C3 haloalkyl, or Ra and Rb, together with a N atom, form a 4-7 membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted with 1-3 halogen atoms;
- R3is
- R4 is H, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl or heteroaryl; and
- when R3 is
- when R3 is
- Rg is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6)cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; Rh is
- In another preferred embodiment, in the general formula (1), R1 is H, F, Cl, Me, Et, vinyl, isopropyl, ethynyl or cyclopropyl.
-
-
-
-
-
-
-
-
- R1a is
- R2a is CH3O-, CH3CH2O-, CF3CH2O- or CHF2CH2O-;
- R3a is
- R4a is H or F; and
- R5a is: H,
-
-
-
-
- wherein, R5b is:
- R5b is: H,
-
- Another purpose of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the compounds of general formulas (1) through (3), the isomers thereof, the crystalline forms thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof of the present invention as active ingredients.
- Still another purpose of the present invention is to provide use of the compounds, the isomers thereof, the crystalline forms thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof of the present invention described above in preparing a medicament for treating RAS-associated diseases.
- Through synthesis of and careful studies on various new compounds with K-RAS G12C inhibitory effects, the inventors found that in the compounds of general formulas (1) through (3), when R5 (or R5a or R5b) is a spiro ring or other substituted heterocyclic ring, the compounds have very high K-RAS G12C inhibitory activity, meanwhile, the pharmacokinetic properties of the compounds are greatly improved, and the in vivo activity of the compounds is enhanced. In another aspect, the inventors found that when position 2 (substituent R4) of acrylamide is substituted with a F atom that is small in size, the compounds also have good K-RAS G12C inhibitory activity and pharmacokinetic properties.
- It should be understood that both the above general description and the following detailed description of the present invention are exemplary and explanatory, and are intended to provide further explanation of the present invention claimed.
- Methods for preparing the compounds of general formulas (1) through (3) of the present invention are hereafter described in detail, but these specific methods do not limit the present invention in any way.
- The compounds of general formulas (1) through (3) described above may be synthesized using standard synthetic techniques or well-known techniques in combination with the methods described herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of the compounds may be obtained synthetically or commercially. The compounds described herein and other related compounds having different substituents may be synthesized using well-known techniques and starting materials, including the methods found in March, ADVANCED ORGANIC CHEMISTRY, 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd Ed., (Wiley 1999). General methods for preparing a compound can be changed by using appropriate reagents and conditions for introducing different groups into the formulas provided herein.
- In one aspect, the compounds described herein are prepared according to methods well known in the art. However, the conditions involved in the methods, such as reactants, solvent, base, amount of the compound used, reaction temperature and time required for the reaction are not limited to the following explanation. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compounds of general formulas (1) through (3), which are prepared using general reaction scheme 1 below:
- In an embodiment of the compound of general formula (1), the preparation may be performed according to general reaction scheme 1, wherein T represents H, F, Cl or I, T1 represents R5, R5a or R5b, T2 represents R3 or R3a, T3 represents R1 or R1a, T4 represents R2 or R2a, and T5 represents R4 or R4a; R1, R1a, R2, R2a, R3, R3a, R4, R4a, R5, R5a and R5b are defined as above, PG represents a protecting group, and X represents boric acid, a borate or a trifluoroborate. As shown in general reaction scheme 1, compound A1 (synthesized according to
WO2018/143315 ) is reacted with compound A2 under basic conditions to give compound A3, compound A3 is reacted with T1H under basic conditions to give compound A4, compound A4 is reacted with T2H under basic conditions to give compound A5; when T = I, compound A5 and T3X are subjected to a coupling reaction to give compound A6, and compound A6 and T4X are subjected to another coupling reaction to give compound A7; when T = H, F or Cl, compound A5 and T4X are subjected to another coupling reaction to directly give compound A7; the protecting group is removed from compound A7 to give compound A8, and compound A8 is reacted with compound A9 to give the target compound A10. - "Pharmaceutically acceptable" herein refers to a substance, such as a carrier or diluent, which will not cause a compound to lose its biological activity or properties. It is relatively non-toxic; for example, when an individual is given a substance, it will not cause unwanted biological effects or interact with any component contained therein in a deleterious manner.
- The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism for drug administration or eliminate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting the compounds of general formulas (1) through (3) with acids, e.g. inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid and nitric acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.
- It should be understood that references to pharmaceutically acceptable salts include solvent addition forms or crystal forms, especially solvates or polymorphs. A solvate contains either stoichiometric or non-stoichiometric amount of solvent and is selectively formed during crystallization with pharmaceutically acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. The solvates of the compounds of general formulas (1) through (3) are conveniently prepared or formed according to the methods described herein. For example, the hydrates of the compounds of general formulas (1) through (3) are conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, wherein the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in both non-solvated and solvated forms. In general, the solvated forms are considered equivalent to the non-solvated forms for purposes of the compounds and methods provided herein.
- In other specific examples, the compounds of general formulas (1) through (3) are prepared into different forms, including but not limited to amorphous, pulverized and nanoparticle forms. In addition, the compound of general formula (1) includes crystalline forms, and may also be polymorphs. Polymorphs include different lattice arrangements of the same elements of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystalline forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may lead to monocrystalline form being dominant.
- In another aspect, the compounds of general formulas (1) through (3) have axial chiralities and/or chiral centers and thus occur in the form of a racemate, racemic mixture, single enantiomer, diastereomeric compound and single diastereomer. Each of these axial chiralities will independently produce two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.
- Unless otherwise stated, the terms used in the present application, including those in the specification and claims, are defined as follows. It must be noted that in the specification and the appended claims, the singular forms "a" and "an" include plural meanings unless the context clearly indicates otherwise. Unless otherwise stated, conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In the present application, "or" or "and" is used to mean "and/or" unless otherwise stated.
- Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including linear and branched groups containing 1 to 6 carbon atoms. Lower alkyl containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, is preferred. As used herein, "alkyl" includes unsubstituted and substituted alkyl, particularly alkyl substituted with one or more halogens. Preferred alkyl is selected from CH3, CH3CH2, CF3, CHF2, CF3CH, iPr, nPr, iBu, nBu and tBu.
- Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon double bonds, including linear and branched groups containing 1 to 6 carbon atoms. Lower alkenyl containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, is preferred.
- Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon triple bonds, including linear and branched groups containing 1 to 6 carbon atoms. Lower alkenyl containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, is preferred.
- Unless otherwise specified, "cycloalkyl" refers to a 3- to 6-membered all-carbon monocyclic aliphatic hydrocarbon group, wherein one or more of the rings may contain one or more double bonds, but none of them has a fully conjugated π-electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, and cyclohexadiene.
- Unless otherwise specified, "alkoxy" refers to an alkyl group that bonds to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are ones having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens. Preferred alkoxy is selected from OCH3, OCF3, CHF2O, CF3CH2O, i-PrO, n-PrO, i-BuO, n-BuO and t-BuO.
- Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N) and it is monocyclic or polycyclic; for example, a monocyclic heteroaryl ring fuses with one or more carbocyclic aromatic groups or other monocyclic heterocyclyl groups. Examples of heteroaryl include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, and pyrrolopyrimidinyl.
- Unless otherwise specified, "heterocycloalkyl" refers to a saturated or partially unsaturated ring system group containing one or more heteroatoms (O, S or N), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized as a ring atom. Unless otherwise stated, the "heterocycloalkyl" ring system may be a monocyclic, bicyclic, spiro or polycyclic ring system. "Heterocycloalkyl" may link to the rest of the molecule through one or more ring carbons or heteroatoms. Examples of "heterocycloalkyl" include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1H,3H) -dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-azaspiro[3.3]heptane, etc.
- Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogenated") before a group name indicates that the group is partially or fully halogenated, that is, substituted in any combination by F, Cl, Br or I, preferably by F or Cl.
- The term "acceptable", as used herein, means that a formula component or an active ingredient does not unduly adversely affect a general therapeutic target's health.
- The terms "treatment," "treatment course," or "therapy", as used herein, include alleviating, inhibiting, or ameliorating a symptom or condition of a disease; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of the disease or symptom, e.g., controlling the progression of the disease or condition; alleviating the disease or symptom; causing the disease or symptom to subside; alleviating a complication caused by the disease or symptom, or preventing or treating a sign caused by the disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, particularly meaning ameliorating the severity, delaying the onset, slowing the progression, or reducing the duration of the disease. Fixed or temporary administration, or continuous or intermittent administration, may be attributed to or associated with the administration.
- The "active ingredient" refers to compounds of general formulas (1) through (3), and pharmaceutically acceptable inorganic or organic salts of the compounds of general formulas (1) through (3). The compounds of the present invention may contain one or more asymmetric centers (axial chirality) and thus occur in the form of a racemate, racemic mixture, single enantiomer, diastereomeric compound and single diastereomer. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each of these asymmetric centers will independently produce two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.
- The terms such as "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and all refer to a compound or composition that, when administered to an individual (human or animal), is capable of inducing a desired pharmacological and/or physiological response by local and/or systemic action.
- The term "administered, administering or administration" refers herein to the direct administration of the compound or composition, or the administration of a prodrug, derivative, analog or the like of the active compound.
- Although the numerical ranges and parameters defining the broad scope of the present invention are approximations, the related numerical values set forth in the specific examples have been present herein as precisely as possible. Any numerical value, however, inherently contains a standard deviation necessarily resulting from certain methods of testing. Herein, "about" generally means that the actual value is within a particular value or range ± 10%, 5%, 1%, or 0.5%. Alternatively, the term "about" indicates that the actual value falls within the acceptable standard error of a mean, as considered by those skilled in the art. All ranges, quantities, values and percentages used herein (e.g., to describe an amount of a material, a length of time, a temperature, an operating condition, a quantitative ratio and the like) are to be understood as being modified by the word "about", except in the experimental examples or where otherwise explicitly indicated. Accordingly, unless otherwise contrarily stated, the numerical parameters set forth in the specification and the appended claims are all approximations that may vary as desired. At the very least, these numerical parameters should be construed as the significant digits indicated or the numerical value obtained using conventional rounding rules.
- Unless otherwise defined in the specification, the scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, the singular nouns used in the specification encompass their plural forms, unless contradicted by context; the plural nouns used also encompass their singular forms.
- The present invention provides a method for using the compound or pharmaceutical composition of the present invention to treat diseases, including but not limited to conditions involving G12C K-Ras, G12C H-Ras and/or G12C N-Ras mutations (e.g., cancer).
- In some embodiments, a method for treating cancer is provided, the method comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition of any of the aforementioned compounds of structural general formulas (1) through (3) protected. In some embodiments, the cancer is mediated by K-Ras, H-Ras and/or G12C N-Ras mutations. In other embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-associated polyposis, or colorectal cancer.
- The compound and the pharmaceutically acceptable salt thereof of the present invention can be prepared into various preparations which include the compound or the pharmaceutically acceptable salt thereof disclosed herein in a safe and effective amount range and a pharmaceutically acceptable excipient or carrier, wherein the "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment and other specific conditions of a treated subject.
- The "pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatible" means that the components of the composition are capable of intermixing with the compound of the present invention and with each other, without significantly diminishing the pharmaceutical efficacy of the compound. Examples of pharmaceutically acceptable excipients or carriers are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oil (e.g., soybean oil, sesame oil, peanut oil or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol or sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- When the compound of the present invention is administered, it may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously) or topically.
- Solid dosage forms for oral administration include capsules, tablets, pills, pulvises and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also include buffers.
- Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may include opacifying agents, and the active compound or compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and wax-based substances. If necessary, the active compound can also be in microcapsule form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances. Besides such inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents. Suspensions, in addition to the active compound, may include suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate and agar, or mixtures of these substances.
- Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for redissolving into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. Dosage forms for topical administration of the compound of the present invention include ointments, pulvises, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants that may be required if necessary.
- The compound of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) to be treated, wherein the administration dose is a pharmaceutically effective administration dose. For a human weighing 60 kg, the daily dose of administration is usually 1-2000 mg, preferably 50-1000 mg. In determining a specific dose, such factors as the route of administration, the health condition of the patient and the like will also be considered, which are well known to skilled physicians.
- The above features mentioned in the present invention or those mentioned in the examples may be combined arbitrarily. All the features disclosed in this specification may be used with any composition form and the various features disclosed in this specification may be replaced with any alternative features that provide the same, equivalent or similar purpose. Thus, unless otherwise expressly stated, the features disclosed are merely general examples of equivalent or similar features.
- Various specific aspects, features and advantages of the compounds, methods and pharmaceutical compositions described above are set forth in detail in the following description, which makes the present invention clear. It should be understood that the detailed description and examples below describe specific embodiments for reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present invention defined herein.
- In all examples, 1H-NMR spectra were recorded with a Vian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts are expressed in δ (ppm); silica gel for separation was 200-300 mesh silica gel if not specified, and the ratio of the eluents was volume ratio. The present invention uses the following abbreviations: CD3OD for deuterated methanol; MeCN for acetonitrile; DCM for dichloromethane; DIPEA for diisopropylethylamine; dioxane for 1,4-dioxane; DMF for dimethylformamide; K3PO4 for potassium phosphate; min for minute; MS for mass spectroscopy; NaH for sodium hydride; NMR for nuclear magnetic resonance; Pd2(dba)3 for tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2 for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; TFA (CF3COOH) for trifluoroacetic acid; TLC for thin layer chromatography; THF for tetrahydrofuran; and Xantphos for 4,5-bis(diphenylphosphane)-9,9-dimethylxanthene.
-
FIG. 1 shows the inhibition of the phosphorylated ERK (pERK) level in cells by compounds. -
- Compound 1-1 (5.5 g, 13.1 mmol) was suspended in dioxane (80 mL). DIPEA (10.1 g, 78.6 mmol) was added under ice bath, followed by 1-2 (3.0 g, 13.1 mmol). The mixture was stirred for 30 min, and stirred at room temperature for 1 h. The reaction was completed as detected by TLC. Water was added, followed by EA for extraction. The organic phase was dried and concentrated, and the residue was slurried with EA to obtain a yellow solid 1-3 (4.5 g, 56% yield).
- 1H NMR (400 MHz, DMSO-d6 ) δ: 8.26 (d, J = 1.5 Hz, 1H), 3.79 (s, 4H), 3.65 (s, 4H), 1.86 (t, J = 5.3 Hz, 4H), 1.39 (s, 9H); MS(ESI): MS (ESI): 611.2 [M+1]+.
- Compound 1-3 (4.5 g, 7.4 mmol) was dissolved in a mixed solution of DMF (40 mL) and THF (40 mL). 1-(2-Methoxyethyl)-4-hydroxypiperidine (2.4 g, 14.8 mmol) and DABCO (0.2 g, 1.5 mmol) were added. The mixture was stirred at room temperature overnight. After the reaction was completed, water was added, followed by EA for extraction. The organic phase was dried and concentrated, and the residue was subjected to column chromatography to obtain compound 1-4 (4.1 g, 76% yield).
- 1H NMR (400 MHz, DMSO-d6 ) δ: 8.14 (s, 1H), 4.99 (ddd, J = 11.7, 8.5, 3.6 Hz, 1H), 3.66 (s, 9H), 3.44 (t, J = 5.8 Hz, 2H), 3.24 (s, 3H), 3.17 (d, J = 5.2 Hz, 1H), 2.77 (dt, J = 9.5, 8.8 Hz, 2H), 2.26 (t, J = 9.8 Hz, 2H), 2.00 (d, J = 12.0 Hz, 2H), 1.84 (d, J = 4.3 Hz, 4H), 1.74 - 1.61 (m, 2H), 1.39 (s, 9H); MS(ESI): 734 .2 [M+1]+.
- Trifluoroethanol (0.9 g, 8.4 mmol) was dissolved in anhydrous DMF (10 mL). NaH was added under ice bath. The mixture was stirred at room temperature for 5 min to obtain sodium trifluoroethoxide. Compound 1-4 (4.1 g, 5.6 mmol) was dissolved in anhydrous THF (40 mL). The solution of sodium trifluoroethoxide in DMF prepared above was added. The mixture was stirred at room temperature overnight. After the reaction was completed, water was added, followed by EA for extraction. The organic phase was dried and concentrated, and the residue was subjected to column chromatography to obtain compound 1-5 (4.5 g, 99% yield). MS (ESI): 814.2 [M+1]+.
- To a single-necked flask were added compound 1-5 (4.1 g, 5.5 mmol), cyclopropylboronic acid (0.5 g, 6.1 mmol), Pd(dppf)Cl2 (0.9 g, 1.1 mmol) and K3PO4 (0.4 g, 1.7 mmol), followed sequentially by MeCN (40 mL), dioxane (40 mL) and H2O (16.5 mL). The mixture was stirred under nitrogen at 100 °C for 5 h. After the reaction was completed, the mixture was subjected to column chromatography to obtain compound 1-6 (2.5 g, 62% yield). MS (ESI): 728.3 [M+1]+.
- To a single-necked flask were added compound 1-6 (2.5 g, 3.4 mmol), 5-methyl-1H-indazole-4-boronic acid (0.9 g, 5.1 mmol), Pd2(dba)3 (0.3 g, 0.4 mmol), Xatphos (0.3 g, 0.7 mmol) and K3PO4 (2.2 g, 10.2 mmol), followed by dioxane (40 mL) and H2O (4 mL). The mixture was stirred under nitrogen at 120 °C overnight. After the reaction was completed, the mixture was subjected to column chromatography to obtain compound 1-7 (1 g, 38% yield). MS (ESI): 780.4 [M+1]+.
- Compound 1-7 (1 g, 1.3 mmol) was dissolved in DCM (15 mL). TFA (5 mL) was added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated, basified with saturated sodium carbonate, and extracted with EA. The organic phase was dried and concentrated to obtain compound 1-8 (0.9 g, 99% yield). MS(ESI): 680.4 [M+1]+.
- Compound 1-8 (150 mg, 0.2 mmol) and 2-fluoroacrylic acid (20 mg, 0.22 mmol) were dissolved in DCM (15 mL). DIPEA (52 mg, 0.4 mmol) and HATU (114 mg, 0.3 mmol) were added under ice bath. The mixture was stirred overnight. After the reaction was completed, the reaction mixture was washed with saturated brine. The organic phase was dried and concentrated, and the residue was subjected to column chromatography to obtain compound 1 (30 mg, 20% yield).
- 1H NMR (400 MHz, CD3OD) δ: 7.47-7.37 (m, 2H), 7.30 (d, J = 8.6 Hz, 1H), 7.24 (s, 1H), 5.52 (d, J= 3.4 Hz, 0.5H), 5.40 (d, J= 3.4 Hz, 0.5H), 5.15 (d, J= 3.4 Hz, 0.5H), 5.11 (d, J= 3.4 Hz, 0.5H), 4.54 (dq, J = 17.7, 8.8 Hz, 1H), 4.23-4.12 (m, 3H), 3.83 (s, 2H), 3.73-3.59 (m, 4H), 3.54 (t, J = 5.2 Hz, 2H), 3.28 (s, 3H), 3.10 (dd, J = 10.1, 6.2 Hz, 2H), 2.88 (s, 2H), 2.85-2.72 (m, 2H), 2.13 (d, J = 26.2 Hz, 5H), 1.97 (dd, J = 11.9, 6.8 Hz, 6H), 1.36 (dt, J = 14.0, 6.6 Hz, 1H), 1.27-1.17 (m, 5H); MS (ESI): 752.4 [M+1]+.
- The target compound 2-341 was obtained using different starting materials according to a synthesis method similar to that in Example 1.
Table 1 Compound Compound structure [M+H]+ Compound Compound structure [M+H]+ 2 698.4 3 734.4 4 684.4 5 738.3 6 792.4 7 747.4 8 691.4 9 727.4 10 694.3 11 712.3 12 728.3 13 708.3 14 722.4 15 736.4 16 718.3 17 748.4 18 759.3 19 802.3 20 812.4 21 812.4 22 800.4 23 801.4 24 799.4 25 801.4 26 706.3 27 734.4 28 767.4 29 786.3 30 770.4 31 766.4 32 752.3 33 756.3 34 756.3 35 734.4 36 756.3 37 738.3 38 756.3 39 735.4 40 753.3 41 761.3 42 779.3 43 762.3 44 780.3 45 714.3 46 732.3 47 713.4 48 731.3 49 781.3 50 799.2 51 698.3 52 715.3 53 716.3 54 734.3 55 748.3 56 715.3 57 714.3 58 730.3 59 746.3 60 746.3 61 708.3 62 750.3 63 766.4 64 694.3 65 738.3 66 736.3 67 674.3 68 692.3 69 687.3 70 705.3 71 731.4 72 749.3 73 701.3 74 719.3 75 745.4 76 763.4 77 715.4 78 733.4 79 741.4 80 759.4 81 771.4 82 789.4 83 755.4 84 773.4 85 783.3 86 801.3 87 754.4 88 772.4 89 757.4 90 775.4 91 759.4 92 777.4 93 773.4 94 791.4 95 773.4 96 791.4 97 701.3 98 719.3 99 745.4 100 763.4 101 773.4 102 791.4 103 759.4 104 777.4 105 773.4 106 791.4 107 787.4 108 805.4 109 662.3 110 680.3 111 704.3 112 722.3 113 706.3 114 724.3 115 706.3 116 723.3 117 750.4 118 768.3 119 746.4 120 764.4 121 746.4 122 764.4 123 702.3 124 720.3 125 746.3 126 764.3 127 744.3 128 762.3 129 730.4 130 748.4 131 774.4 132 792.4 133 772.4 134 790.4 135 730.4 136 748.4 137 773.4 138 792.4 139 693.3 140 719.4 141 737.3 142 687.3 143 705.3 144 717.3 145 735.3 146 717.3 147 735.3 148 745.4 149 763.4 150 702.3 151 720.3 152 717.3 153 735.3 154 745.4 155 763.4 156 702.3 157 727.4 158 729.3 159 715.4 160 759.4 161 729.4 162 715.4 163 729.4 164 743.4 165 689.3 166 703.4 167 743.3 168 705.3 169 723.3 170 731.4 171 700.4 172 719.3 173 719.3 174 731.4 175 731.4 176 737.3 177 715.4 178 733.3 179 745.4 180 751.3 181 700.4 182 700.4 183 715.4 184 715.4 185 689.4 186 689.4 187 703.4 188 703.4 189 717.4 190 717.4 191 733.4 192 733.4 193 733.4 194 733.4 195 745.4 196 745.4 197 745.4 198 745.4 199 751.3 200 751.3 201 719.3 202 719.3 203 731.4 204 731.3 205 737.3 206 737.3 207 729.4 208 729.4 209 731.4 210 731.4 211 747.4 212 747.4 213 759.4 214 759.4 215 715.4 216 729.4 217 701.4 218 715.4 219 705.3 220 719.3 221 687.3 222 701.4 223 691.3 224 705.3 225 677.4 226 688.4 227 703.4 228 707.3 229 705.3 230 719.4 231 714.3 232 703.4 233 717.4 234 719.4 235 733.4 236 721.4 237 701.4 238 712.3 239 785.3 240 717.3 241 765.3 242 726.3 243 717.3 244 730.4 245 715.4 246 715.4 247 715.4 248 715.4 249 726.3 250 726.3 251 731.4 252 731.4 253 759.4 254 759.4 255 744.4 256 744.4 257 726.3 258 726.3 259 731.4 260- 731.4 261 735.3 262 735.3 263 749.4 264 749.4 265 731.4 266 745.4 267 737.3 268 729.4 269 743.4 270 727.4 271 717.3 272 717.3 273 719.3 274 719.3 275 731.4 276 731.4 277 744.4 278 744.4 279 688.3 280 731.4 281 731.4 282 688.3 283 702.3 284 690.3 285 697.3 286 715.4 287 727.4 288 741.4 289 741.4 290 755.4 291 755.4 292 755.4 293 755.4 294 729.4 295 729.4 296 715.4 297 715.4 298 729.4 299 729.4 300 729.4 301 729.4 302 741.4 303 741.4 304 690.3 305 706.3 306 721.3 307 750.3 308 702.3 309 746.3 310 751.3 311 753.3 312 751.3 313 751.3 314 737.3 315 737.3 316 739.3 317 753.3 318 768.3 319 768.3 320 687.3 321 701.3 322 701.3 323 715.3 324 729.3 325 729.3 326 741.4 327 733.4 328 733.4 329 745.4 330 661.4 331 661.4 332 673.4 333 697.4 334 697.4 335 709.4 336 673.3 337 687.4 338 745.4 339 701.4 340 701.4 341 713.4 - The compounds of the present application may have axial chirality. Compounds with axial chirality can be resolved to obtain two chiral isomers.
- Compound 142 (50 mg) was dissolved in ethanol (2 mL) at a concentration of 25 mg/mL. The volume for each injection was 500 µL. Conditions for preparative chromatography: CHIRALPAK AD-H (20 × 250 mm, 5 µm) chromatography column; mobile phase: ethanol-n-hexane (40/60); flow rate: 12 mL/min; wavelength of detection: 254 nm. The stepwise eluate was concentrated by rotary evaporation and dried to obtain two chiral isomers 142-a and 142-b of compound 142:
- a first chiral isomer: 142-a; retention time on the chromatography column: 6.662 min; and
- a second chiral isomer: 142-b; retention time on the chromatography column: 10.831 min.
-
Compounds 171, 174 and 270 were chirally resolved using a similar resolution procedure to obtain their two chiral isomers 171-a/171-b, 174-a/174-b and 270-a/270-b, respectively. Their retention times on the chromatography column are as follows:Table 2. Conditions for and results of chiral resolution of compounds 171, 174 and 270Compound Conditions for resolution Results of resolution 171 Same as those for compound 142 a first chiral isomer: 171-a; retention time on the chromatography column: 7.481 min; and a second chiral isomer: 171-b; retention time on the chromatography column: 12.770 min. 174 Same as those for compound 142 a first chiral isomer: 174-a; retention time on the chromatography column: 8.994 min; and a second chiral isomer: 174-b; retention time on the chromatography column: 14.583 min. 270 Same as those for compound 142 except that the mobile phase is ethanol-n-hexane (30/70)a first chiral isomer: 270-a; retention time on the chromatography column: 7.280 min; and a second chiral isomer: 270-b; retention time on the chromatography column: 12.962 min. - Other compounds in the present application can also be chirally resolved using a similar method.
- H358 cells were seeded in a 24-well plate. After one day of growth, a test compound (at a concentration of 1 µM) was added. After 24 h of action of the compound, the cells were lysed, and the cell lysate was transferred to a 96-well ELISA plate. The levels of pERK and ERK in the lysate were measured using an ELISA kit (abcam 176660). The ratio of pERK to ERK was calculated and compared with that of the DMSO group, and the percentage of inhibition of pERK activity by the compound was calculated. The results are shown in Table 3 below.
Table 3. Inhibitory activity of the compounds of the present invention against the pERK level in H358 cells Compound Inhibition rate (%) Compound Inhibition rate (%) Compound Inhibition rate (%) 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 ++ 8 ++ 9 +++ 10 ++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 ++ 17 +++ 18 ++ 19 ++ 20 +++ 21 +++ 22 ++ 23 +++ 24 ++ 25 +++ 26 ++ 27 ++ 28 ++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 ++ 38 +++ 39 +++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 +++ 49 +++ 50 +++ 51 +++ 52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 +++ 59 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64 ++ 65 +++ 66 ++ 67 ++ 68 ++ 69 +++ 70 +++ 71 +++ 72 +++ 73 +++ 74 +++ 75 +++ 76 +++ 77 ++ 78 ++ 79 ++ 80 ++ 81 +++ 82 +++ 83 +++ 84 +++ 85 +++ 86 ++ 87 +++ 88 ++ 89 +++ 90 +++ 91 +++ 92 +++ 93 +++ 94 +++ 95 +++ 96 +++ 97 ++ 98 ++ 99 +++ 100 +++ 101 +++ 102 +++ 103 +++ 104 ++ 105 +++ 106 ++ 107 ++ 108 ++ 109 +++ 110 +++ 111 +++ 112 ++ 113 +++ 114 +++ 115 ++ 116 ++ 117 +++ 118 +++ 119 ++ 120 ++ 121 ++ 122 ++ 123 +++ 124 +++ 125 +++ 126 +++ 127 +++ 128 +++ 129 +++ 130 +++ 131 +++ 132 +++ 133 +++ 134 +++ 135 ++ 136 ++ 137 +++ 138 +++ 139 +++ 140 +++ 141 +++ 142 +++ 143 +++ 144 +++ 145 +++ 146 +++ 147 +++ 148 ++ 149 ++ 150 +++ 151 +++ 152 +++ 153 +++ 154 +++ 155 ++ 156 +++ 157 +++ 158 +++ 159 +++ 160 +++ 161 +++ 162 +++ 163 +++ 164 +++ 165 +++ 166 +++ 167 +++ 168 +++ 169 ++ 170 ++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176 ++ 177 +++ 178 +++ 179 +++ 180 +++ 181 +++ 182 +++ 183 +++ 184 +++ 185 +++ 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192 +++ 193 +++ 194 +++ 195 +++ 196 +++ 197 +++ 198 +++ 199 +++ 200 +++ 201 +++ 202 +++ 203 +++ 204 +++ 205 ++ 206 ++ 207 +++ 208 +++ 209 +++ 210 +++ 211 +++ 212 +++ 213 ++ 214 ++ 215 +++ 216 +++ 217 +++ 218 +++ 219 +++ 220 +++ 221 +++ 222 +++ 223 +++ 224 +++ 225 +++ 226 +++ 227 +++ 228 +++ 229 +++ 230 ++ 231 ++ 232 +++ 233 +++ 234 +++ 235 +++ 236 +++ 237 +++ 238 +++ 239 ++ 240 +++ 241 ++ 242 +++ 243 +++ 244 +++ 245 +++ 246 +++ 247 +++ 248 +++ 249 ++ 250 ++ 251 +++ 252 +++ 253 +++ 254 +++ 255 +++ 256 +++ 257 +++ 258 +++ 259 +++ 260 +++ 261 +++ 262 +++ 263 +++ 264 +++ 265 +++ 266 +++ 267 +++ 268 +++ 269 +++ 270 +++ 271 +++ 272 +++ 273 +++ 274 +++ 275 +++ 276 +++ 277 +++ 278 +++ 279 +++ 280 +++ 281 +++ 282 +++ 283 ++ 284 +++ 285 ++ 286 +++ 287 +++ 288 +++ 289 +++ 290 +++ 291 +++ 292 +++ 293 +++ 294 +++ 295 +++ 296 +++ 297 +++ 298 +++ 299 +++ 300 +++ 301 +++ 302 +++ 303 +++ 304 ++ 305 ++ 306 +++ 307 +++ 308 +++ 309 +++ 310 ++ 311 +++ 312 +++ 313 +++ 314 +++ 315 +++ 316 +++ 317 +++ 318 +++ 319 +++ 320 +++ 321 +++ 322 +++ 323 +++ 324 +++ 325 +++ 326 +++ 327 +++ 328 +++ 329 +++ 330 +++ 331 +++ 332 +++ 333 +++ 334 +++ 335 +++ 336 +++ 337 +++ 338 +++ 339 +++ 340 +++ 341 +++ 142-a +++ 142-b ++ 171-a +++ 171-b +++ 174-a +++ 174-b ++ 270-a +++ 270-b +++ B +++ C +++ + indicates an inhibition rate less than or equal to 50%
++ indicates an inhibition rate from 50% to 90%
+++ indicates an inhibition rate greater than 90%. - 2500 H358 cells were seeded in a 96-well ultra-low attachment plate (corning, 7007). After one day of growth, a serially diluted compound (a maximum concentration of 5 µM, 5-fold dilution, a total of five doses) was added. Three days after the addition of the compound, Cell Titer Glow (Promega, G9681) was added to evaluate pellet growth, and the IC50 value was calculated. The results are shown in Table 4 below.
Table 4. Antiproliferative activity of the compounds of the present invention against H358 cells Compound IC50 Compound IC50 Compound IC50 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 ++ 8 ++ 9 +++ 10 ++ 11 +++ 12 +++ 13 ++ 14 ++ 15 +++ 16 ++ 17 +++ 18 ++ 19 ++ 20 +++ 21 +++ 22 ++ 23 +++ 24 ++ 25 +++ 26 ++ 27 ++ 28 ++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 ++ 38 ++ 39 +++ 40 +++ 41 +++ 42 ++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 ++ 49 +++ 50 +++ 51 +++ 52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 +++ 59 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64 ++ 65 +++ 66 ++ 67 ++ 68 ++ 69 +++ 70 ++ 71 +++ 72 +++ 73 +++ 74 +++ 75 +++ 76 +++ 77 ++ 78 ++ 79 ++ 80 ++ 81 +++ 82 +++ 83 +++ 84 +++ 85 ++ 86 ++ 87 +++ 88 ++ 89 +++ 90 +++ 91 +++ 92 +++ 93 +++ 94 +++ 95 +++ 96 +++ 97 ++ 98 ++ 99 +++ 100 +++ 101 +++ 102 +++ 103 +++ 104 ++ 105 +++ 106 ++ 107 ++ 108 ++ 109 +++ 110 +++ 111 +++ 112 ++ 113 +++ 114 +++ 115 ++ 116 ++ 117 +++ 118 +++ 119 +++ 120 ++ 121 +++ 122 ++ 123 +++ 124 +++ 125 +++ 126 +++ 127 +++ 128 +++ 129 +++ 130 +++ 131 +++ 132 +++ 133 +++ 134 +++ 135 ++ 136 ++ 137 +++ 138 +++ 139 +++ 140 +++ 141 +++ 142 +++ 143 +++ 144 +++ 145 +++ 146 +++ 147 +++ 148 ++ 149 ++ 150 +++ 151 ++ 152 +++ 153 +++ 154 +++ 155 ++ 156 +++ 157 +++ 158 +++ 159 +++ 160 +++ 161 +++ 162 +++ 163 +++ 164 +++ 165 +++ 166 +++ 167 ++ 168 +++ 169 ++ 170 ++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176 ++ 177 +++ 178 +++ 179 +++ 180 ++ 181 +++ 182 +++ 183 +++ 184 +++ 185 +++ 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192 +++ 193 +++ 194 +++ 195 +++ 196 +++ 197 +++ 198 +++ 199 ++ 200 ++ 201 +++ 202 +++ 203 ++ 204 ++ 205 ++ 206 ++ 207 +++ 208 +++ 209 +++ 210 +++ 211 +++ 212 +++ 213 ++ 214 ++ 215 +++ 216 +++ 217 +++ 218 +++ 219 +++ 220 +++ 221 +++ 222 +++ 223 +++ 224 +++ 225 +++ 226 +++ 227 +++ 228 +++ 229 +++ 230 ++ 231 ++ 232 +++ 233 +++ 234 +++ 235 +++ 236 +++ 237 +++ 238 ++ 239 ++ 240 +++ 241 ++ 242 +++ 243 +++ 244 +++ 245 +++ 246 +++ 247 +++ 248 +++ 249 ++ 250 ++ 251 +++ 252 +++ 253 ++ 254 ++ 255 +++ 256 +++ 257 ++ 258 ++ 259 +++ 260 +++ 261 +++ 262 +++ 263 +++ 264 +++ 265 +++ 266 +++ 267 +++ 268 +++ 269 +++ 270 +++ 271 +++ 272 +++ 273 +++ 274 +++ 275 +++ 276 +++ 277 +++ 278 +++ 279 +++ 280 +++ 281 +++ 282 +++ 283 ++ 284 +++ 285 ++ 286 +++ 287 +++ 288 +++ 289 +++ 290 +++ 291 +++ 292 +++ 293 +++ 294 +++ 295 +++ 296 +++ 297 +++ 298 +++ 299 +++ 300 +++ 301 +++ 302 +++ 303 +++ 304 ++ 305 ++ 306 +++ 307 +++ 308 +++ 309 +++ 310 ++ 311 +++ 312 +++ 313 +++ 314 +++ 315 +++ 316 +++ 317 +++ 318 +++ 319 +++ 320 +++ 321 +++ 322 +++ 323 +++ 324 +++ 325 +++ 326 +++ 327 +++ 328 +++ 329 +++ 330 +++ 331 +++ 332 +++ 333 +++ 334 +++ 335 +++ 336 +++ 337 +++ 338 +++ 339 +++ 340 +++ 341 +++ 142-a +++ 142-b ++ 171-a +++ 171-b +++ 174-a +++ 174-b ++ 270-a +++ 270-b +++ B +++ C +++ + indicates the IC50 of the compound is greater than 1 µM
++ indicates the IC50 of the compound is from 0.3 to 1 µM
+++ indicates the IC50 of the compound is less than 0.3 µM. - As can be seen from the data in Tables 3 and 4, the antiproliferative activity of most of the compounds of the present invention against H358 cells is less than 0.3 µM, and when R5 (or R5a or R5b) is a spiro ring or other substituted heterocyclic ring, the compounds have very high K-RAS G12C inhibitory activity.
Compounds - The compounds were administered by intravenous injection at a dose of 2 mg/kg and oral gavage at a dose of 10 mg/kg (0.5% CMC-Na suspension). 15 male ICR mice were selected for each group, and each mouse was subjected to blood collection at 3 discrete time points, with 3 mice per time point. The time points of sampling were as follows: before the administration, and at 5 min, 15 min, 30 min, 1 h, 3 h, 5 h, 8 h, 12 h and 24 h after the administration. 80 µL of blood was collected from the eye sockets or the hearts of the mice at each of the time points after the administration. All whole blood samples were collected in tubes containing EDTA K2 and centrifuged (1500-1600 rmp) at 4 °C for 10 min to isolate plasma, which was then stored in a refrigerator at -90 to -60 °C for sample analysis. The compound concentration in the plasma was determined by liquid chromatography-tandem mass spectrometry, and the corresponding pharmacokinetic parameters were obtained according to a plasma concentration-time curve.
Table 5. Pharmacokinetic parameters of compounds in mice Compound Route of administration Dose (mg/kg) t ½ (h) Tmax (h) Cmax (ng/mL) AUC 0-t (ng.h/L) Vss (mL/kg) Cl (mL/h/kg) F (%) 1 iv 2 4.31 1 2557 13987 782 140 NA po 10 6.94 4 1543 20304 NA NA 29.0 131 iv 2 4.12 0.5 2346 11340 2104 112 NA po 10 5.86 2 1824 22315 NA NA 39.4 142 iv 2 3.31 0.083 13067 51995 187 38.5 NA po 10 3.89 2 6730 45952 NA NA 17.7% 171 iv 2 4.85 0.083 4910 26500 505 75.6 NA po 10 3.93 2 3320 35700 NA NA 26.9 B iv 2 4.47 0.083 2883 7822 1010 252 NA po 10 3.74 2 1300 10348 -NA NA 26.5 C iv 2 4.02 0.083 3210 20200 481 99 NA po 10 3.38 0.5 3110 24800 NA NA 24.6 NA indicates data are not available; - As can be seen from the above table, compared to compound B, compound 131 has good oral absorption properties, and has improved metabolic parameters such as half-life (t½), maximum plasma concentration (Cmax), area under the drug-time curve (AUC0-t), and oral bioavailability. It should be particularly noted that, compared to the reference compound C in the patent (Example 65 of
WO2018/143315 ),compound 171 has better metabolic parameters, andcompound 142 also has significantly improved metabolic parameters such as Cmax and AUC0-t, indicating that the metabolic properties of the compound are well improved after the amino groups on the side chain are cyclized. The metabolic properties of the compounds similar tocompounds 131 and 171 in the present application are also significantly improved. Good oral absorption properties are of great significance in improving the efficacy of drugs, reducing the dose of administration and reducing the costs. - Human pancreatic cancer Mia PaCa-2 cells were cultured conventionally in 1640 medium containing 10% fetal bovine serum in a 37 °C/5% CO2 incubator. After passage, the cells were collected when they reached the desired amount. 1×107 Mia PaCa-2 cells were injected into the left dorsal side of each nude mouse, and the animals were randomly grouped for administration after tumors grew to 150 mm3. The groups are as follows: 1) a solvent control group of 8 mice; and 2) compound 1 group, compound 2 group, compound 5 group, compound 31 group, compound 131 group,
compound 142 group,compound 171 group, compound B group and compound C group, with 8 mice per group. Mice in the solvent control group were subjected to intragastric administration of 0.5% CMC-Na once daily; mice in compound 1 group, compound 2 group, compound 5 group, compound 31 group, compound 131 group,compound 142 group,compound 171 group, compound B group and compound C group were subjected to intragastric administration of a suspension of a compound in 0.5% CMC-Na once daily. On Tuesday and Thursday each week, tumor volumes and body weight of the mice were measured, and the nude mice were sacrificed on day 21 of administration. The test results are shown in Table 6 below.Table 6. Experimental therapeutic effects of compounds on graft tumors of human pancreatic cancer Mia PaCa-2 in nude mice Compound Dose (mg/kg) Administration regimen Anti-tumor effect 1 10 qd∗21 39% regression 2 10 qd∗21 23% regression 5 10 qd∗21 30% regression 31 10 qd∗21 32% regression 131 10 qd∗21 37 % regression 142 10 qd∗21 35 % regression 171 10 qd∗21 38 % regression B 10 qd∗21 25 % regression C 10 qd∗21 8% regression - As can be seen from the data in the table above, the compounds of the present invention have high in vivo antitumor activity; a tumor can regress after 21 consecutive days of administration at 10 mg/kg/day;
compounds - H358 cells were plated on to a 24-well plate at 2 × 105 cells/well. Serially diluted compounds including AMG510, MRTX849,
compound 142 andcompound 171 were added. After overnight incubation, cells were lysed, and proteins were quantified and subjected to gel electrophoresis. - The results of the phosphorylated ERK (pERK) level assay by western blot are shown in
FIG. 1 . - As can be seen from the results in
FIG. 1 , thecompounds
Claims (17)
- A compound with a structure as shown in general formula (1), isomers thereof, crystalline forms thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof:R1 is H, halogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl;R2 is C1-C3 alkoxy, C1-C3 haloalkoxy or -NRaRb, wherein Ra and Rb are independently H, Cl-C3 alkyl or C1-C3 haloalkyl, or Ra and Rb, together with a N atom, form a 4-7 membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted with 1-3 halogen atoms;R3 isR4 is H, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl or heteroaryl; andwhen R3 iswhen R3 is
- The compound according to claim 1, wherein in the general formula (1), R1 is H, F, Cl, Me, Et, isopropyl, vinyl, ethynyl or cyclopropyl.
- A compound with a structure as shown in general formula (2), isomers thereof, crystalline forms thereof pharmaceutically acceptable salts thereof hydrates thereof or solvates thereof:R2a is CH3O-, CH3CH2O-, CF3CH2O- or CHF2CH2O-;R3aisR4a is H or F; andR5a is: H,
- A compound with a structure as shown in general formula (3), isomers thereof, crystalline forms thereof pharmaceutically acceptable salts thereof hydrates thereof or solvates thereof:wherein, R5b is:R5b is: H,
- A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the compounds of general formulas (1) through (3), the isomers thereof, the crystalline forms thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof according to any one of claims 1-15 as active ingredients.
- Use of the compounds of general formulas (1) through (3), the isomers thereof, the crystalline forms thereof, the pharmaceutically acceptable salts thereof, the hydrates thereof or the solvates thereof according to any one of claims 1-15 in preparing a medicament for treating RAS-associated diseases.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911386239.6A CN113045570A (en) | 2019-12-27 | 2019-12-27 | Spiro-containing quinazoline compounds |
CN202010486384.8A CN113754659A (en) | 2020-06-01 | 2020-06-01 | Spiro-containing quinazoline compounds |
PCT/CN2020/139530 WO2021129820A1 (en) | 2019-12-27 | 2020-12-25 | Spiro ring-containing quinazoline compound |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4083042A1 true EP4083042A1 (en) | 2022-11-02 |
Family
ID=76573713
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP20905322.2A Pending EP4083042A1 (en) | 2019-12-27 | 2020-12-25 | Spiro ring-containing quinazoline compound |
Country Status (10)
Country | Link |
---|---|
US (1) | US20230002382A1 (en) |
EP (1) | EP4083042A1 (en) |
JP (1) | JP2023508482A (en) |
KR (1) | KR20220122662A (en) |
CN (1) | CN114929704A (en) |
AU (1) | AU2020414943A1 (en) |
BR (1) | BR112022010267A2 (en) |
CA (1) | CA3162106A1 (en) |
MX (1) | MX2022006609A (en) |
WO (1) | WO2021129820A1 (en) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11932633B2 (en) | 2018-05-07 | 2024-03-19 | Mirati Therapeutics, Inc. | KRas G12C inhibitors |
JP2022517222A (en) | 2019-01-10 | 2022-03-07 | ミラティ セラピューティクス, インコーポレイテッド | KRAS G12C inhibitor |
JP2022546043A (en) | 2019-08-29 | 2022-11-02 | ミラティ セラピューティクス, インコーポレイテッド | KRAS G12D inhibitor |
CA3152025A1 (en) | 2019-09-24 | 2021-04-01 | David BRIERE | Combination therapies |
EP4076418A4 (en) | 2019-12-20 | 2024-01-24 | Mirati Therapeutics Inc | Sos1 inhibitors |
IL301062A (en) | 2020-09-03 | 2023-05-01 | Revolution Medicines Inc | Use of sos1 inhibitors to treat malignancies with shp2 mutations |
PE20231207A1 (en) | 2020-09-15 | 2023-08-17 | Revolution Medicines Inc | INDOLIC DERIVATIVES AS RAS INHIBITORS IN CANCER TREATMENT |
US20240109893A1 (en) * | 2020-12-22 | 2024-04-04 | Shanghai Kechow Pharma, Inc. | Preparation and application method of heterocyclic compounds as kras inhibitor |
WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
WO2022266206A1 (en) | 2021-06-16 | 2022-12-22 | Erasca, Inc. | Kras inhibitor conjugates |
IL310291A (en) * | 2021-07-23 | 2024-03-01 | Theras Inc | Compositions and methods for inhibition of ras |
WO2023008462A1 (en) | 2021-07-27 | 2023-02-02 | 東レ株式会社 | Medicament for treatment and/or prevention of cancer |
AR127308A1 (en) | 2021-10-08 | 2024-01-10 | Revolution Medicines Inc | RAS INHIBITORS |
WO2023114954A1 (en) | 2021-12-17 | 2023-06-22 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
WO2024081674A1 (en) | 2022-10-11 | 2024-04-18 | Aadi Bioscience, Inc. | Combination therapies for the treatment of cancer |
WO2024102421A2 (en) | 2022-11-09 | 2024-05-16 | Revolution Medicines, Inc. | Compounds, complexes, and methods for their preparation and of their use |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013159698A1 (en) * | 2012-04-26 | 2013-10-31 | 深圳信立泰药业股份有限公司 | Fused ring quinazoline hydroximic acid compound and use thereof as anti-tumour drug |
CN103772411B (en) * | 2013-04-28 | 2016-08-03 | 复旦大学 | Sulfur-bearing 6-furyl quinazoline-4-amines and its production and use |
US10414757B2 (en) * | 2015-11-16 | 2019-09-17 | Araxes Pharma Llc | 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof |
CN110088098B (en) * | 2016-01-26 | 2022-04-15 | 中国医学科学院药物研究所 | Quinazolinone PARP-1 inhibitor and preparation method, pharmaceutical composition and application thereof |
JOP20190186A1 (en) * | 2017-02-02 | 2019-08-01 | Astellas Pharma Inc | Quinazoline compound |
JP2021176819A (en) * | 2018-07-31 | 2021-11-11 | アステラス製薬株式会社 | Pharmaceutical composition comprising quinazoline compound as active ingredient |
JP2021176820A (en) * | 2018-07-31 | 2021-11-11 | アステラス製薬株式会社 | Pharmaceutical composition comprising quinazoline compound as active ingredient |
KR20210097715A (en) * | 2018-11-29 | 2021-08-09 | 아락세스 파마 엘엘씨 | Compounds for the treatment of cancer and methods of use thereof |
CN111499634B (en) * | 2019-01-31 | 2023-05-12 | 贝达药业股份有限公司 | Quinazoline compound and application thereof in medicine |
WO2020177629A1 (en) * | 2019-03-01 | 2020-09-10 | 劲方医药科技(上海)有限公司 | Spiro-substituted pyrimidine-fused cyclic compound, preparation method therefor and medical use thereof |
CN112110918B (en) * | 2019-06-21 | 2023-08-22 | 劲方医药科技(上海)有限公司 | Spiro substituted pyrimido cyclic compounds, process for their preparation and their use in medicine |
-
2020
- 2020-12-25 AU AU2020414943A patent/AU2020414943A1/en active Pending
- 2020-12-25 KR KR1020227023548A patent/KR20220122662A/en active Search and Examination
- 2020-12-25 CA CA3162106A patent/CA3162106A1/en active Pending
- 2020-12-25 BR BR112022010267A patent/BR112022010267A2/en unknown
- 2020-12-25 WO PCT/CN2020/139530 patent/WO2021129820A1/en unknown
- 2020-12-25 EP EP20905322.2A patent/EP4083042A1/en active Pending
- 2020-12-25 CN CN202080090796.8A patent/CN114929704A/en active Pending
- 2020-12-25 MX MX2022006609A patent/MX2022006609A/en unknown
- 2020-12-25 JP JP2022539444A patent/JP2023508482A/en active Pending
- 2020-12-25 US US17/767,034 patent/US20230002382A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
CN114929704A (en) | 2022-08-19 |
US20230002382A1 (en) | 2023-01-05 |
WO2021129820A1 (en) | 2021-07-01 |
JP2023508482A (en) | 2023-03-02 |
MX2022006609A (en) | 2022-07-05 |
BR112022010267A2 (en) | 2022-08-16 |
CA3162106A1 (en) | 2021-07-01 |
AU2020414943A1 (en) | 2022-08-04 |
KR20220122662A (en) | 2022-09-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP4083042A1 (en) | Spiro ring-containing quinazoline compound | |
CN115335379B (en) | Spirocyclic quinazoline compounds | |
CN113767103B (en) | Novel spirocyclic K-Ras G12C inhibitors | |
WO2021129824A1 (en) | New-type k-ras g12c inhibitor | |
EP2947086B1 (en) | Novel fused pyrimidine compound or salt thereof | |
WO2020259432A1 (en) | Kras-g12c inhibitor | |
CA3213029A1 (en) | Parp inhibitor containing piperazine structure, preparation method therefor and pharmaceutical use thereof | |
CN116390728B (en) | Quinazoline derivative, preparation method and application thereof | |
CN113045570A (en) | Spiro-containing quinazoline compounds | |
CN114736214B (en) | Sesquiterpene derivative, pharmaceutical composition thereof, and preparation method and application thereof | |
EP4265620A1 (en) | Novel camptothecin derivative, composition containing same, and use thereof | |
CN111646986B (en) | Nicotinic acid derivative and preparation method and application thereof | |
CN113754659A (en) | Spiro-containing quinazoline compounds | |
KR102606167B1 (en) | Fluorine-containing substituted benzothiophene compounds, pharmaceutical compositions and applications thereof | |
CN113880804A (en) | Novel benzimidazole compounds | |
CN107163047B (en) | Sophoridine amine derivative and preparation method and application thereof | |
CN116783194A (en) | Spirocyclic quinazoline derivatives | |
EP4159731A1 (en) | New pyrazine compound | |
CN109942566B (en) | Isonicotinic acid derivative and preparation method and application thereof | |
KR101071359B1 (en) | 2-methyl-2-alkyl-6-amido-2h-benzopyran derivatives having anti-cancer activity | |
EP4332104A1 (en) | Fused ring compound as wee-1 inhibitor, and preparation method therefor and use thereof | |
TW202306955A (en) | Naphthyridine derivative as ATR inhibitor and method for preparing same | |
CN116693470A (en) | Histamine H3 receptor inhibitor and medical application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20220727 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61P 35/00 20060101ALI20240219BHEP Ipc: A61K 31/517 20060101ALI20240219BHEP Ipc: C07D 471/10 20060101AFI20240219BHEP |